||This article's lead section may not adequately summarize key points of its contents. (October 2013)|
|Jmol-3D images||Image 1|
|Molar mass||115.15 g mol−1|
|S-phrases||(S2) S26 S28 S36/37/39 S45 S60 S61|
|R/S statement||R23/24/25 R34 R43 R50/53|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
|(what is: / ?)|
Methylisothiazolinone and other isothiazolinone-derived biocides are utilized for controlling microbial growth in water-containing solutions. Two of the most widely used isothiazolinone biocides are 5-chloro-2-methyl-4-isothiazolin-3-one (chloromethylisothiazolinone or CMIT) and 2-methyl-4-isothiazolin-3-one (methylisothiazolinone or MIT), which are the active ingredients in a 3:1 mixture (CMIT:MIT) sold commercially as Kathon. Kathon is supplied to manufacturers as a concentrated stock solution containing from 10-15% of CMIT/MIT. For applications the recommended use level is from 6 ppm to 75 ppm active isothiazolones. Biocidal applications range from industrial water storage tanks to cooling units, in processes as varied as mining, paper manufacturing, metalworking fluids and energy production. In addition, one isothiazolinone, Sea-Nine 211 (4,5-dichloro-2-n-octyl-4-isothiazolino-3-one, DCOI), has quickly replaced tributyltin as the antifouling agent of choice in ship hull paint. A recent study reported the presence of DCOI in both port water and sediment samples in Osaka, Japan, especially in weakly circulating mooring areas. Of environmental concern, DCOI levels predicted in marinas are now considered a threat to various marine invertebrate species. Isothiazolinones are also extremely toxic to fish. The widespread use of isothiazolinones in industrial settings has resulted in a very large number of reported cases of human occupational exposure, sometimes reaching epidemic proportions. This occurs primarily, but not exclusively, when workers are exposed to stock solutions during the dilution process, usually resulting in chemical burns, contact dermatitis, and allergic sensitization. Inhalation exposure is also very common.
Non-occupational exposure to isothiazolinones by the general population also occurs, albeit at much lower concentrations. These compounds can be detected in air-conditioned indoor air and are present in a very large number of commonly used cosmetics. “Leave-on” cosmetics (hand-creams, lotions, etc.) contain 15 parts per million (100 micromolar) of combined CMIT/MIT. Kathon has also been used to control slime in the manufacture of paper products that contact food. In addition, this product serves as an antimicrobial agent in latex adhesives and in paper coatings that also contact food. The long-term consequences of low-level chronic exposure to isothiazolinones on the central nervous system have not been thoroughly investigated.
Some studies have shown MIT to be allergenic and cytotoxic, and this has led to some concern over its use. In 2002, there was an in vitro study of the neurotoxicity of MIT in the department of Neurobiology at the University of Pittsburgh. In that study, it was shown that a short exposure (10 min) to concentrations of MIT of 30-100 micromolar (or 4-12 parts per million) were lethal to mature neurons in tissue culture, but not to other brain cells, such as astrocytes (support cells). The lethal actions of MIT were due to its ability to liberate the metal zinc from intracellular metal-binding sites. The liberated zinc, in turn, triggered a cell death cascade in neurons that was characterized by the sequential activation of extracellular signal-regulated kinase (ERK) and NADPH oxidase. This activity led to production of reactive oxygen species (free radicals), DNA damage and the overactivation of the DNA repair enzyme poly(ADP-ribose)polymerase, or PARP. Overactivation of PARP has been linked by many investigators to cell death due to its consumption of reduced equivalents and depletion of cellular energy sources (ATP). Additional studies from the same laboratory have observed that CMIT may be significantly (30-100 times) more potent than the MIT observations. All these studies were performed on rat brain cells in culture.
The CFTA (Cosmetic, Toiletry, and Fragrance Association) issued a response statement asserting that MIT is safe in cosmetic formulas. The CFTA response is as follows: "The abstract on Methylisothiazolinone (MI), presented at the Cell Biology 2004 meeting of the American Society for Cell Biology (ASCB) lacks a credible scientific basis in suggesting that MI could be a safety issue for consumers using personal care products. In determining the safety of any ingredient, a major factor is exposure. Cosmetic exposure is so much lower than what is presented in this abstract as to make the study meaningless for safety evaluation purposes regarding cosmetic products. The experiments conducted with MI on extracted rat nerve cells in laboratory containers do not remotely resemble the possible consumer exposure to this preservative. Reports have suggested that safety testing with animals has demonstrated that application of MI does not result in systemic toxicity to the preservative. Clinical and functional effects on the nervous system have reportedly not been observed in relevant safety tests." However, none of these safety tests have been published in the peer-reviewed scientific literature.
The results from the abstract presented at the ASCB meeting were later published in a peer-reviewed scientific journal.
The CFTA response continues: "MI is a preservative that has been specifically approved for use as a biocide by the US Environmental Protection Agency (EPA), by Japan, and by the European Commission for use in cosmetics. It is used at very low levels, parts per million (one part per million = one drop in a 55 gallon drum) in cosmetic products, including shampoos and other products. MI was reviewed by the Cosmetic Ingredient Review (CIR)* in 1992 as a component of a preservative mixture with methylchloroisothiazolinone (MCI) and found safe for use in cosmetics. Cosmetics are regulated under the Food, Drug and Cosmetic Act, which is enforced by the U.S. Food and Drug Administration (FDA). The Food and Drug Administration (FDA) has abundant legal authority to regulate the safety of cosmetic products."
A report released by the European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers (SCCNFP) in 2003 concluded that insufficient information was available to allow for an adequate risk assessment analysis of MIT. In 2004, after receiving additional studies, committee said "The SCCNFP is of the opinion that the proposed use of Methylisothiazolinone as a preservative at a maximum concentration of 0.01% (100 ppm) in the finished cosmetic product does not pose a risk to the health of the consumer."
Allergic contact dermatitis
Methylisothiazolinone is commonly used in products in conjunction with methylchloroisothiazolinone, a mixture sold under the registered trade name Kathon CG. A common indication of sensitivity to Kathon CG is allergic contact dermatitis. Sensitization to this family of preservatives was observed as early as the late 1980s. Due to increased use of isothiazolinone-based preservatives in recent years, an increase in reported incidences of contact allergy to this product have been reported, and in 2013 it was dubbed the 2013 Contact Allergen of the Year.
On December 13, 2013 the trade group, Cosmetics Europe, following discussions with the European Society of Contact Dermatitis (ESCD), recommended to its members "that the use of Methylisothiazolinone (MIT) in leave-on skin products including cosmetic wet wipes is discontinued. This action is recommended in the interests of consumer safety in relation to adverse skin reactions. It is recommended that companies do not wait for regulatory intervention under the Cosmetics Regulation but implement this recommendation as soon as feasible."
On March 27, 2014, the European Commission’s Scientific Committee on Consumer Safety issued an opinion on the safety of Methylisothiazolinone. This report only considered the issue of contact sensitization. The Committee concluded:
“Current clinical data indicate that 100 ppm MI in cosmetic products is not safe for the consumer.
For leave-on cosmetic products (including ‘wet wipes’), no safe concentrations of MI for induction of contact allergy or elicitation have been adequately demonstrated.
For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the view of induction of contact allergy. However, no information is available on elicitation.”
Physiopathological effects of MIT on developing neurons
MIT and its closely related analog, chloromethylisothiazolinone or CMIT, affect the ability of young or developing neurons to grow processes (axons and dendrites) in tissue culture. The specific protein affected by MIT is called focal adhesion kinase, or FAK. Normal FAK function is required for the growth of axons and dendrites. FAK has to be modified by a process called phosphorylation to perform its function, so phosphates are added to FAK’s amino acid chain (a process called tyrosine phosphorylation). MIT inhibits the tyrosine phosphorylation of FAK by another kinase called Src, preventing the growth of axons and dendrites, at least in culture. These findings were published in the Journal of Pharmacology and Experimental Therapeutics. The toxic actions of MIT on developing neurons occurs at much lower concentrations than those inducing lethal injury (1-3 micromolar). CMIT is even more potent, working at concentrations as low as 0.1 micromolar. One micromolar is approximately 0.115 parts per million.
- Collier PJ. Ramsey A. Waigh RD. Douglas KT. Austin P. Gilbert P. (1990). "Chemical reactivity of some isothiazolone biocides". Journal of Applied Bacteriology 69 (4): 578–584. doi:10.1111/j.1365-2672.1990.tb01551.x. PMID 2292521.
- Harino H. Mori Y. Yamaguchi Y. Shibata K. Senda T. (2005). "Monitoring of antifouling booster biocides in water and sediment from the port of Osaka, Japan". Arch Environ Cont Toxicol 48 (3): 303–310. doi:10.1007/s00244-004-0084-2. PMID 15750770.
- Bellas J. (2006). "Comparative toxicity of alternative antifouling biocides on embryos and larvae of marine invertebrates". Sci Total Environ 367 (2–3): 573–85. doi:10.1016/j.scitotenv.2006.01.028. PMID 16545431.
- Rohm and Haas, Toxicology Department, “Evaluation of the toxicity of Kathon biocide,” August, 1984
- Podmore P. (1998). "An epidemic of isothiazolinone sensitization in a flax spinning mill". Contact Dermatitis 38 (3): 165–1666. doi:10.1111/j.1600-0536.1998.tb05687.x. PMID 9536412.
- Isaksson M. Gruvberger B. Bruze M., M (2004). "Occupational contact allergy and dermatitis from methylisothiazolinone after contact with wall covering glue and after a chemical burn from a biocide". Dermatitis 15 (4): 201–205. doi:10.2310/6620.2004.04017. PMID 15842065.
- Environmental Protection Agency (1998). R.E.D. Facts, Methylisothiazolinone. Publication EPA-738-F-98-008
- Nagorka R. Rosskamp E. Seidel K. [Evaluation of humidifier units within the scope of room climate modification]. [German] Offentliche Gesundheitswesen. 52:168-73, 1990
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- A. C. De Groot, A. Herxheimer: "Isothiazolinone Preservative: Cause Of A Continuing Epidemic Of Cosmetic Dermatitis", The Lancet, Volume 333, Issue 8633, Pages 314-316 (1989).
- Shen Du, BethAnn McLaughlin, Sumon Pal, Elias Aizenman (2002). "In vitro neurotoxicity of methylisothiazolinone, a commonly used industrial and household biocide, proceeds via a zinc and extracellular signal-regulated kinase mitogen-activated protein kinase-dependent pathway". Journal of Neuroscience 22 (17): 7408–7416. PMID 12196562.
- K. He, J. Huang, C. F. Lagenaur, E. Aizenman (2006). "Methylisothiazolinone, a neurotoxic biocide, disrupts the association of Src family tyrosine kinases with focal adhesion kinase in developing cortical neurons". J. Pharmacol. Exp. Therap. 317 (3): 1320–1329. doi:10.1124/jpet.106.103044. PMID 16547166.
- European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers (SCCNFP)
- Hannuksela, M. (1986). "Rapid increase in contact allergy to Kathon CG in Finland". Contact dermatitis 15 (4): 211–214. doi:10.1111/j.1600-0536.1986.tb01338.x. PMID 3802805.
- De Groot, A. C.; Weyland, J. W. (1988). "Kathon CG: A review". Journal of the American Academy of Dermatology 18 (2 Pt 1): 350–358. PMID 3279090.
- Castanedo-Tardana, M. P.; Zug, K. A. (2013). "Methylisothiazolinone". Dermatitis : contact, atopic, occupational, drug 24 (1): 2–6. doi:10.1097/DER.0b013e31827edc73. PMID 23340392.
- Cosmetics Europe Recommendation on MIT 
- European Society of Contact Dermatitis 
- Cosmetics Europe Recommendation on MIT 
- European Commission Scientific Committee on Consumer Safety Opinion on Methylisothiazolinone (P94) Submission II (Sensitization only) SCCS/1521/13 
- Reregistration Eligibility Decision of MIT by US EPA
- Record in the Household Products Database of NLM
- Material Safety Data Sheet for product containing 0.1-1% MIT
- Commission Scientific Committee on Consumer Safety Opinion on Methylisothiazolinone (P94) Submission II (Sensitization only) SCCS/1521/13